Mu Zepeng, Randolph Haley E, Aguirre-Gamboa Raúl, Ketter Ellen, Dumaine Anne, Locher Veronica, Brandolino Cary, Liu Xuanyao, Kaufmann Daniel E, Barreiro Luis B, Li Yang I
medRxiv. 2024 Dec 12:2024.12.05.24318552. doi: 10.1101/2024.12.05.24318552.
Only a third of immune-associated loci from genome-wide association studies (GWAS) colocalize with expression quantitative trait loci (eQTLs). To learn about causal genes and mechanisms at the remaining loci, we created a unified single-cell chromatin accessibility (scATAC-seq) map in peripheral blood comprising a total of 282,424 cells from 48 individuals. Clustering and topic modeling of scATAC data identified discrete cell-types and continuous cell states, which helped reveal disease-relevant cellular contexts, and allowed mapping of genetic effects on chromatin accessibility across these contexts. We identified 37,390 chromatin accessibility QTLs (caQTL) at 10% FDR across eight cell groups and observed extensive sharing of caQTLs across immune cell contexts, finding that fewer than 20% of caQTLs are specific to a single cell type. Notably, caQTLs colocalized with ∼50% more GWAS loci compared to eQTLs, helping to nominate putative causal genes for many unexplained loci. However, most GWAS-caQTL colocalizations had no detectable downstream regulatory effects on gene expression levels in the same cell type. We find evidence that the higher rates of colocalization between caQTLs and GWAS signals reflect missing disease-relevant cellular contexts among existing eQTL studies. Thus, there remains a pressing need for identifying disease-causing cellular contexts and for mapping gene regulatory variation in these cells.
全基因组关联研究（GWAS）中只有三分之一的免疫相关基因座与表达数量性状基因座（eQTL）共定位。为了了解其余基因座的因果基因和机制，我们创建了一个外周血统一的单细胞染色质可及性图谱（scATAC-seq），该图谱包含来自48个人的总共282,424个细胞。scATAC数据的聚类和主题建模确定了离散的细胞类型和连续的细胞状态，这有助于揭示与疾病相关的细胞背景，并允许在这些背景下绘制遗传效应对染色质可及性的影响。我们在八个细胞组中以10%的错误发现率（FDR）确定了37,390个染色质可及性数量性状基因座（caQTL），并观察到caQTL在免疫细胞背景中的广泛共享，发现不到20%的caQTL是特定于单一细胞类型的。值得注意的是，与eQTL相比，caQTL与约50%更多的GWAS基因座共定位，这有助于为许多无法解释的基因座提名推定的因果基因。然而，大多数GWAS-caQTL共定位对同一细胞类型中的基因表达水平没有可检测到的下游调节作用。我们发现有证据表明，caQTL与GWAS信号之间较高的共定位率反映了现有eQTL研究中缺失的与疾病相关的细胞背景。因此，迫切需要确定致病的细胞背景，并绘制这些细胞中的基因调控变异图谱。
